The Genotype of the Original Wiskott Phenotype

Binder, Vera; Albert, Michael H.; Kabus, Maria; Bertone, Marko; Meindl, Alfons; Belohradsky, Bernd H.

doi:10.1056/nejmoa062520

Cited by 25 publications

(12 citation statements)

References 20 publications

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“…The crucial role of many ABPs is evident in the diseases caused by mutations in genes encoding ABPs. For example, the Wiskott‐Aldrich syndrome, a disease caused by mutations in the WASP gene, affects the immune system, and entails eczema and thrombocytopenia [Binder et al, ].…”

Section: Intrinsically Disordered Abps In Disease and Infectionmentioning

confidence: 99%

Intrinsic Structural Disorder in Cytoskeletal Proteins

et al. 2013

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Cytoskeleton, the internal scaffold of the cell, displays an exceptional combination of stability and dynamics. It is composed of three major filamentous networks, microfilaments (actin filaments), intermediate filaments (neurofilaments), and microtubules. Together, they ensure the physical and structural stability of the cell, whereby also mediating its large-scale structural rearrangements, motility, stress response, division, and internal transport. All three cytoskeletal systems are built upon the same basic design: they have a central repetitive scaffold assembled from folded building elements, surrounded and regulated by accessory regions/proteins that regulate its formation and mediate its countless interactions with its environment, serving to send regulatory signals to and from the cytoskeleton. Here, we elaborate on the idea that the opposing features of stability and dynamics are also manifest in the dichotomy of the structural status of its components, the core being highly structured and the accessory proteins/regions being highly disordered, and are responsible for most of the regulatory (post-translational) input promoting adaptive responses and providing dynamics necessary for each of the cytoskeletal systems. This pattern entails special consequences, in which the manifold functional advantages of structural disorder, most pronounced in regulatory and signaling functions, are all exploited by nature. (MTs), and it provides the internal scaffold (skeleton) of the cell. It can be considered as a very special organelle, which represents a unique combination of stability and dynamics, physical rigidity and flexibility, long-time persistence and rapid, cataclysmic rearrangements. By providing a special microenvironment, the cytoskeleton ensures the physical separation of cellular constituents, thus segregating and directing cellular activities. It bridges molecular (nano-m) and cellular (micro-m) distances and represent the tracks of transport of cellular constituents over large distances. It provides the locomotive force of cell migration, it drives clustering of membrane proteins, drives cell division and the formation of protrusions the cell uses for exploring its environment. Apparently it does it by a combination of a physically rigid but inherently unstable central scaffold and a flexible and rather variable outer layer of accessory proteins/regions. Due to its central importance in cell physiology, the cytoskeleton is involved in many diseases, ranging from cancer to neurodegeneration [Pajkos et al., 2012;Raychaudhuri et al., 2009;Uversky et al., 2008]. Our central theme here is that multifaceted and highly dynamic behavior is enabled by structural disorder in all three major cytoskeletal constituents, also reflecting their increasing complexity from NFs to the actin cytoskeleton (Supporting Information Table S1, Table I). Intermediate filaments (IFs) have three principal components, IF-L(ight), IF-M(edium), and IF-H(igh), all three of which form an extended coiled-coil structures, from which...

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Section: Intrinsically Disordered Abps In Disease and Infectionmentioning

confidence: 99%

Intrinsic Structural Disorder in Cytoskeletal Proteins

et al. 2013

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“…The gene for WAS (WAS) was identified on the X chromosome (position Xp11.22-p11.23) by positional cloning, 3 and the family that was initially described by Wiskott was confirmed to have a deletion of two nucleotides at positions 73-74 (AC73-74del) of WAS, resulting in frameshift and premature termination of the protein. 4 WAS protein (WASp) is a multifaceted protein associated with several clinical disorders. Mutations that result in absent WASp cause classic WAS characterized by thrombocytopenia with small platelets, eczema, recurrent infections because of immunodeficiency, and an increased incidence of autoimmunity and malignancies.…”

Section: Introductionmentioning

confidence: 99%

Wiskott‐Aldrich syndrome: a comprehensive review

Massaad

Ramesh

Geha

2013

Annals of the New York Academy of Sciences

300

264

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Wiskott-Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency characterized by microthrombocytopenia, eczema, recurrent infections, and an increased incidence of autoimmunity and malignancies. The disease is caused by mutations in the WAS gene expressed exclusively in hematopoietic cells. WAS protein (WASp) is a multidomain protein that exists in complex with several partners that play important roles in its function. WASp belongs to a family of proteins that relay signals from the surface of the cell to the actin cytoskeleton. Mutations in the WAS gene have various effects on the level of WASp, which, in turn, correlates with the severity of the disease. In addition to WAS, mutations in the WAS gene can result in the mild variant X-linked thrombocytopenia, or in X-linked neutropenia, characterized by neutropenia with myelodysplasia. The absence of functional WASp leads to a severe clinical phenotype that can result in death if not diagnosed and treated early in life. The treatment of choice with the best outcome is hematopoietic stem cell transplantation, preferably from a matched related donor.

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“…In 1994, WAS was linked to mutations in a gene on the short arm of the X chromosome, encoding Wiskott-Aldrich syndrome protein (WASP). A frameshift mutation in the WAS gene was found in family members of the originally described patients [70]. The symptomatic individuals were all male, consistent with an X-linked recessive inheritance.…”

Section: Clinical Manifestationsmentioning

confidence: 72%

Current Strategies in Diagnosis of Inherited Storage Pool Defects

Sandrock

Zieger²

2010

Transfus Med Hemother

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Inherited platelet defects lead to bleeding symptoms of varying severity. Typically, easy bruising, petechiae, epistaxis, and mucocutaneous bleeding are observed in affected patients. The platelet defects are classified into disorders affecting either platelet surface receptors or intracellular organelles of platelets. The latter are represented by platelet storage pool diseases (SPD) which share a defect of platelet granules. Platelet a-granules, d-granules, or both may be affected resulting in the clinical picture of a-SPD (e.g. Gray platelet syndrome, Quebec platelet disorder, arthrogryposis, renal dysfunction, and cholestasis syndrome), d-SPD (e.g. Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, Griscelli syndrome), or ad-SPD (e.g. X-linked thrombocytopenia, Wiskott-Aldrich syndrome). Diagnosis of SPD is very extensive and requires platelet aggregation and flow cytometry analyses with interpretation from a specialist. Many of these disorders share common treatments, however, efficacy can vary between different patients. Therapy regiments with tranexamic acid, DDAVP, activated FVIIa, and platelet transfusions have been published. Stem cell or bone marrow transplantations are preserved for severe defects. Here, we describe the pathophysiology, clinical manifestations, and diagnosis of the major human SPDs.

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The Genotype of the Original Wiskott Phenotype

Cited by 25 publications

References 20 publications

Intrinsic Structural Disorder in Cytoskeletal Proteins

Intrinsic Structural Disorder in Cytoskeletal Proteins

Wiskott‐Aldrich syndrome: a comprehensive review

Current Strategies in Diagnosis of Inherited Storage Pool Defects

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